Dosage & Administration
By using PrescriberAI, you agree to the AI Terms of Use.
Sympazan Prescribing Information
- Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation[see, and
5.1 Risks from Concomitant Use with OpioidsConcomitant use of benzodiazepines, including SYMPAZAN®, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe SYMPAZAN®concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when SYMPAZAN®is used with opioids
[see Drug Interactions (7.1)].].7.1 OpioidsThe concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAAsites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation
[see Warnings and Precautions (5.1)]. - The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction[see].
5.2 Abuse, Misuse, and AddictionThe use of benzodiazepines, including SYMPAZAN, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death
[see Drug Abuse and Dependence (9.2)].
Before prescribing SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of SYMPAZAN, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SYMPAZAN along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. - The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinueSYMPAZAN or reduce the dosage[seeand
2.2 Discontinuation or Dosage Reduction of SYMPAZANTo reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue SYMPAZAN or reduce the dosage
.Taper by decreasing the total daily dosage by 5-10 mg/day on a weekly basis until discontinued. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly[see Warnings and Precautions (5.3)and Drug Abuse and Dependence (9.3)].].5.3 Dependence and Withdrawal ReactionsTo reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN or reduce the dosage
[see Dosage and Administration (2.2)].
Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.Acute Withdrawal Reactions
The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures)[see Drug Abuse and Dependence (9.3)].Protracted Withdrawal Syndrome
In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months[see Drug Abuse and Dependence (9.3)].
Warning and Precautions (
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including clobazam. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. SYMPAZAN should be discontinued if an alternative etiology for the signs or symptoms cannot be established
SYMPAZAN® is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older.
- For doses above 5 mg/day, administer in two divided doses ()
2.1 Dosing InformationA daily dose of SYMPAZAN®greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g., 5 to 20 mg in 30 kg or less weight group) has been shown to be effective, although effectiveness increases with increasing dose
[see Clinical Studies (14)].Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.Table 1: Recommended Total Daily Dosing by Weight Group30 kgor LessBody WeightGreater than30 kg Body WeightStarting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg - Patients weighing 30 kg or less: Initiate at 5 mg daily, and titrate as tolerated up to 20 mg daily ()
2.1 Dosing InformationA daily dose of SYMPAZAN®greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g., 5 to 20 mg in 30 kg or less weight group) has been shown to be effective, although effectiveness increases with increasing dose
[see Clinical Studies (14)].Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.Table 1: Recommended Total Daily Dosing by Weight Group30 kgor LessBody WeightGreater than30 kg Body WeightStarting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg - Patients weighing greater than 30 kg: Initiate at 10 mg daily, and titrate as tolerated up to 40 mg daily ()
2.1 Dosing InformationA daily dose of SYMPAZAN®greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g., 5 to 20 mg in 30 kg or less weight group) has been shown to be effective, although effectiveness increases with increasing dose
[see Clinical Studies (14)].Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.Table 1: Recommended Total Daily Dosing by Weight Group30 kgor LessBody WeightGreater than30 kg Body WeightStarting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg - Dosage adjustment is needed in following groups:
○ Geriatric patients (,2.4 Dosage Adjustments in Geriatric PatientsPlasma concentrations at any given dose are generally higher in geriatric patients
[see Clinical Pharmacology (12.3)].Therefore, the starting dosage should generally be 5 mg/day for all geriatric patients. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21[see Use in Specific Populations (8.5)].)8.5 Geriatric UseClinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, dosage modification is recommended
[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
○ Known CYP2C19 poor metabolizers ()2.5 Dosage Adjustments in CYP2C19 Poor MetabolizersIn CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased
[see Clinical Pharmacology (12.5)].Therefore, the starting dosage should be 5 mg/day in patients known to be CYP2C19 poor metabolizers. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21[see Use in Specific Populations (8.6)].
○ Mild or moderate hepatic impairment; no information for severe hepatic impairment (,2.6 Dosage Adjustments in Patients with Hepatic ImpairmentSYMPAZAN®is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of SYMPAZAN®. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dosage should be 5 mg/day (regardless of weight). Then proceed slowly with dosing escalations; titrate patients according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21. There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment. Therefore, no dosing recommendation can be given for those patients
[see Use in Specific Populations (8.8), Clinical Pharmacology (12 .3)].)8.8 Hepatic ImpairmentSYMPAZAN®is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9
) [see Dosage and Administration (2.6)].There is inadequate information about metabolism of SYMPAZAN®in patients with severe hepatic impairment[see Clinical Pharmacology (12.3)]. - Can be taken with or without food ()
2.3 Important Administration InstructionsInstruct patients and/or caregivers to read the “Instructions for Use” carefully for complete directions on how to properly dose and administer SYMPAZAN®oral films.
Apply SYMPAZAN®on top of the tongue where it adheres and dissolves.
SYMPAZAN® oral film can be taken with or without food
[see Clinical Pharmacology (12.3)].Do not administer with liquids. As the film dissolves, saliva should be swallowed in a normal manner, but the patient should refrain from chewing, spitting or talking.Only one oral film should be taken at a time; if a second film is needed to complete the dosage, it should not be taken until the first film has completely dissolved.
- Do not administer with liquids ()
2.3 Important Administration InstructionsInstruct patients and/or caregivers to read the “Instructions for Use” carefully for complete directions on how to properly dose and administer SYMPAZAN®oral films.
Apply SYMPAZAN®on top of the tongue where it adheres and dissolves.
SYMPAZAN® oral film can be taken with or without food
[see Clinical Pharmacology (12.3)].Do not administer with liquids. As the film dissolves, saliva should be swallowed in a normal manner, but the patient should refrain from chewing, spitting or talking.Only one oral film should be taken at a time; if a second film is needed to complete the dosage, it should not be taken until the first film has completely dissolved.
SYMPAZAN® Oral Film: Thin, white, rectangular, orally dissolving film strips:
- 5 mg imprinted with C5
- 10 mg imprinted with C10
- 20 mg imprinted with C20
- Pregnancy: Based on animal data, may cause fetal harm ()
8.1 PregnancyPregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN®, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN®enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/Risk Summary
Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal[see Warnings and Precautions (5.9)and Clinical Considerations].Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data). Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [see Animal Data].
Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15% -20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse Reactions
Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly[see Warnings and Precautions (5.9)].DataHuman Data
Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.Animal Data
In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Oral administration of clobazam (0, 50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low-effect dose for adverse effects on preand postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.